Hematopoietic stem cell transplantation (HSCT) is currently the only therapeutic modality with curative potential in patients with myelodysplastic syndromes (MDS). Relapse (in advanced MS), regimen- related toxicity (RRT) and non-relapse-mortality (MRS) have remained causes of treatment failure. RRT increases with age, a concern in MDS patients with a median age at diagnosis of 65-70 years. Patients with myelofibrosis (MF) frequently are in a similar age range and have limited therapeutic options. The long-term goal of this project is to improve outcome with HSCT in patients with MDS and MF. To reduce NRM, new regimens with reduced to improve outcome with HSCT in patients with MDS and MF. To reduce NRM, new regimens with reduced toxicity for related or unrelated transplants will be developed. Specifically, 1) patients with "less advanced" MDS will receive busulfan (BU) targeted to plasma levels of 800-900 ng/mL plus cyclophosphamide (CY), g-CSF mobilized peripheral blood stem cells (PBSC), and post-grafting methotrexate (MTX) and cyclosporine (CSP); 2) patients with "advanced" MDS will be treated with either a) targeted BU (800-900 ng/mL) plus fludarabine, G-CSF mobilized blood stem cells (PBSC), and post-grafting methotrexate (MTX) and cyclosporine (CSP); 2) patients with "advanced" MDS will be treated with either a) targeted BU (800- 900 NG/mL) plus fludaribine, G-CSF mobilized PBSC, and MTX/CSP (patients <66 years old; CD33-; .30X10/9 WBC/L), or b) mylotarg (anti- CD33-conjugated calicheamicin), fludarabine, 200 cGy of total body irradiation (TBI), G-CSF mobilized PBSC and mycophenolate mofetil (MMF)/CSF (patients with MF, >65 years old; CD33+; <30x10/9WBC/L; medical contraindications to conventional regimens); 3) patients with MF, <66 years old, will receive targeted BU and CY, G- CSF mobilized PBSC, and MMF/CSP (related) or MTX/CSP (unrelated donors). MF patients will also undergo sequential marrow scanning and biopsies to determine the kinetics of regression of MF; 4) high risk and older patients with MDS or MF will be treated with a non-myeloablative regimen (fludarabine+ 200 cGy TBI) and MMF/CSP post-transplant, relying on a graft-vs-host effect for disease eradication. Results from those studies will be considered in the design of subsequent protocols under this Project. These treatment strategies are expected to reduce RRT and NRM in patients with MDS and MF without increasing the relapse rate, and thereby further improve disease-free survival.